Method of treatment and pharmaceutical composition

ABSTRACT

The invention relates to a method for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, myocardial infarction and its sequelae, supraventricular and ventricular arrhythmias, atrial fibrillation or atrial flutter, atherosclerosis, angina (whether stable or ustable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetessecondary aldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and pulmonary hypertension, renal failure conditions, such as diabetic nephropathy,glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, Raynaud&#39;s disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer&#39;s), and stroke, comprising administering a therapeutically effective amount of combination of (i) the AT 1 -antagonists valsartan or a pharmaceutically acceptable salt thereof and (ii) a Calcium channel blocker or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal in need of such treatment and to corresponding pharmaceutical combination composition.

This is a divisional application of U.S. application Ser. No. 09/349,654filed Jul. 8, 1999, now U.S. Pat. No. 6,204,281.

The present invention relates to a pharmaceutical composition comprisingas active ingredients

(i) the AT₁ receptor antagonist(S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine(valsartan) of formula (I)

or a pharmaceutically acceptable salt thereof and

(ii) a Calcium channel blocker (CCB) or a pharmaceutically acceptablesalt thereof and

(iii) a pharmaceutically acceptable carrier.

Valsartan is disclosed in EP 0443983 A.

A CCB useful in said combination is preferably selected from the groupconsisting of amlodipine, diltiazem, felodipine, fendiline, flunarizine,gallopamil, isradipine, lacidipine, mibefradil, nicardipine, nifedipine,niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine,nivaldipine, ryosidine, tiapamil and verapamil, and in each case, apharmaceutically acceptable salt thereof. All these drugs aretherapeutically used as CCBs, e.g. as anti-hypertensive, anti-anginapectoris or anti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or,e.g. dependent on the specific CCB, a pharmaceutically acceptable saltthereof. Especially preferred is amlodipine or a pharmaceuticallyacceptable salt, especially the besylate, thereof.

The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic centre, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic centre. The compounds having at least one acid group (forexample COOH) can also form salts with bases. Corresponding internalsalts may furthermore be formed, if a compound of formula comprises e.g.both a carboxy and an amino group.

Preferred salts of corresponding CCBs are amlodipine besylate, diltiazemhydrochloride, fendiline hydrochloride, flunarizine di-hydrochloride,gallopamil hydrochloride, mibefradil di-hydrochloride, nicardipinehydrochloride, and verapamil hydrochloride.

The vasoconstrictive effects of angiotensin II are produced by itsaction on the non-striated smooth muscle cells, the stimulation of theformation of the adrenergenic hormones epinephrine and norepinephrine aswell as the increase of the activity of the sympathetic nervous systemas a result of the formation of norepinephrine. Angiotensin II also hasan influence on the electrolytic balance, produces e.g. antinatriureticand antidiuretic effects in the kidney and thereby promotes the releaseof, on the one hand, the vasopressin peptide from the pituitary glandand, on the other hand, of aldosterone from the adrenal glomerulosa. Allthese influences play an important part in the regulation of bloodpressure, in increasing both circulating volume and peripheralresistance. Angiotensin II is also involved in cell growth and migrationand in extracellular matrix formation.

Angiotensin II interacts with specific receptors on the surface of thetarget cell. It has been possible to identify receptor subtypes whichare termed e.g. AT₁- and AT₂-receptors. In recent times great effortshave been made to identify substances that bind to the AT₁-receptor.Such active ingredients are often termed angiotensin II antagonists.Because of the inhibition of the AT₁-receptor such antagonists can beused e.g. as antihypertensives or for the treatment of congestive heartfailure.

Angiotensin II antagonists are therefore understood to be those activeingredients which bind to the AT₁-receptor subtype.

Prolonged and uncontrolled hypertensive vascular disease ultimatelyleads to a variety of pathological changes in target organs such as theheart and kidney. Sustained hypertension can lead as well to anincreased occurrence of stroke. Therefore, there is a strong need toevaluate the efficacy of antihypertensive therapy, an examination ofadditional cardiovascular endpoints, beyond those of blood pressurelowering, to get further insight into the benefits of combinedtreatment.

The nature of hypertensive vascular diseases is multifactorial. Undercertain circumstances, drugs with different mechanisms of action havebeen combined. However, just considering any combination of drugs havingdifferent mode of action does not necessarily lead to combinations withadvantageous effects.

AT₁ antagonist and CCB reduce intracellular calcium by different andcomplementary mechanisms and facilitate the vasodilator effects ofnitric oxide, being particularly effective in reversing endotheliumdysfunction.

All the more surprising is the experimental finding that the combinedadministration of the AT₁-antagonist valsartan or a pharmaceuticallyacceptable salt thereof and a CCB or a pharmaceutically acceptable saltthereof results not only in a synergistic therapeutic effect but also inadditional benefits resulting from combined treatment such as asurprising prolongation of efficacy and a broader variety of therapeutictreatment. This includes hemodynamic, antiproliferative, antithromboticand antiatherogenic properties.

The measurement of cardiac mass to assess treatment-induced regressionof hypertrophy provided data to support a supra-additive effect ofcombination of the present invention. Left ventricular hypertrophy is anindependent risk factor for the development of myocardial infarction.Thus, effective blood pressure lowering coupled with the ability toregress or prevent the development of left ventricular hypertrophy hasan impact on two important and contributing factors for heart failure.

Further benefits are that lower doses of the individual drugs to becombined according to the present invention can be used to reduce thedosage, for example, that the dosages need not only often be smaller butare also applied less frequently, or can be used to diminish theincidence of side effects. This is in accordance with the desires andrequirements of the patients to be treated.

It can be shown that combination therapy with valsartan and a calciumchannel blocker results in a more effective antihypertensive therapy(whether for malignant, essential, reno-vascular, diabetic, isolatedsystolic, or other secondary type of hypertension) through improvedefficacy as well as a greater responder rate. The combination is also beuseful in the treatment or prevention of (acute and chronic) congestiveheart failure, left ventricular dysfunction and hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation or atrial flutter. It canfurther be shown that a valsartan+CCB therapy proves to be beneficial inthe treatment and prevention of myocardial infarction and its sequelae.A valsartan plus CCB combination is also useful in treatingatherosclerosis, angina (whether stable or unstable), and renalinsufficiency (diabetic and non-diabetic). Furthermore, combinationtherapy using valsartan and a CCB can improve endothelial dysfunction,thereby providing benefit in diseases in which normal endothelialfunction is disrupted such as heart failure, angina pectoris anddiabetes. Furthermore, the combination of the present invention may beused for the treatment or prevention of secondary aldosteronism, primaryand secondary pulmonary hyperaldosteronism, primary and pulmonaryhypertension, renal failure conditions, such as diabetic nephropathy,glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria ofprimary renal disease, and also renal vascular hypertension, diabeticretinopathy, the management of other vascular disorders, such asmigraine, Raynaud's disease, luminal hyperplasia, cognitive dysfunction(such as Alzheimer's), and stroke.

The person skilled in the pertinent art is fully enabled to select arelevant test model to prove the hereinbefore and hereinafter indicatedtherapeutic indications.

Representative studies are carried out with a combination of valsartanand amlodipine, e.g. applying following methodology. All experiments areperformed in spontaneously hypertensive rats (SHR) supplied by TaconicFarms, Germantown, N.Y. (Tac:N(SHR)fBR). A radiotelemetric device (DataSciences International, Inc., St. Paul, Minn.) is implanted into thelower abdominal aorta of all test animals between the ages of 14 to 16weeks of age. All SHR are allowed to recover from the surgicalimplantation procedure for at least 2 weeks prior to the initiation ofthe experiments. The radiotransmitter is fastened ventrally to themusculature of the inner abdominal wall with a silk suture to preventmovement. Cardiovascular parameters are continuously monitored via theradiotransmitter and transmitted to a receiver where the digitizedsignal is then collected and stored using a computerized dataacquisition system. Blood pressure (mean arterial, systolic anddiastolic pressure) and heart rate are monitored in conscious, freelymoving and undisturbed SHR in their home cages. The arterial bloodpressure and heart rate are measured every 10 minutes for 10 seconds andrecorded. Data reported for each rat represent the mean values averagedover a 24 hour period and are made up of the 144-10 minute samplescollected each day. The baseline values for blood pressure and heartrate consist of the average of three consecutive 24 hour readings takenprior to initiating the drug treatments. All rats are individuallyhoused in a temperature and humidity controlled room and are maintainedon a 12 hour light/dark cycle.

In addition to the cardiovascular parameters, weekly determinations ofbody weight also are recorded in all rats. Since all treatments areadministered in the drinking water, water consumption is measured fivetimes per week. Valsartan and amlodipine doses for individual rats arethen calculated based on water consumption for each rat, theconcentration of drug substance in the drinking water, and individualbody weights. All drug solutions in the drinking water are made up freshevery three to four days.

Upon completion of the 6 week treatment, SHR are anesthetized and theheart rapidly removed. After separation and removal of the atrialappendages, left ventricle and left plus right ventricle (total) areweighed and recorded. Left ventricular and total ventricular mass arethen normalized to body weight and reported. All values reported forblood pressure and cardiac mass represent the group mean+sem.

Valsartan and amlodipine are administered via the drinking water eitheralone or in combination to SHR beginning at 18 weeks of age andcontinued for 6 weeks. Based on a factorial design, seven (7) treatmentgroups are used to evaluate the effects of combination therapy on bloodpressure and heart rate. Treatment groups consist of valsartan alone indrinking water at a concentration of 240 mg/liter (high dose),amlodipine alone at a concentration of 120 mg/liter (high dose),valsartan (120 mg/liter)+amlodipine (60), valsartan (120)+amlodipine(120), valsartan (240)+amlodipine (60), valsartan (240)+amlodipine (120)and a vehicle control group on regular drinking water. Thus, 4 groups ofSHR receive combination therapy.

Studies have been performed in SHR and demonstrate that the addition ofa CCB confers additional benefit over that of valsartan monotherapy. TheArea Under the Curve (AUC) for blood pressure reflects the changes inresponse to 6 week treatment in conscious SHR. Upon completion of the 6week treatment period, hearts are removed for assessment of leftventricle mass and normalized to body weight.

The available results indicate an unexpected beneficial effect of acombination according to the invention.

Further representative studies are carried out with a combination ofvalsartan and a CCB, especially a non-DHP representative thereof, suchas verapamil.

Diabetic renal disease is the leading cause of end-stage renal diseases.Hypertension is a major determinant of the rate of progression ofdiabetic diseases, especially diabetic nephropathy. It is known that areduction of blood pressure may slow the reduction of diabeticnephropathy and proteinuria in diabetic patients, however dependent onthe kind of antihypertensive administered.

In diabetic SHRs the presence of hypertension is an importantdeterminant of renal injury, manifesting in functional changes such asalbuminuria and in ultrastructural injury. For example, diabetic SHRsshow ventricular hypertrophy and develop nephropathy resulting in suddendeath events. Acordingly, the use of this animal model is well-appliedin the art and suitable for evaluating effects of drugs on thedevelopment of diabetic renal diseases. There is a strong need toachieve a significant increase of the survival rate by treatment ofhypertension in diabetes especially in NIDDM. It is known that CCBs arenot considered as first line antihypertensives e.g. in NIDDM treatment.Though some kind of reduction of blood pressure may be achieved withCCBs, they may not be indicated for the treatment of renal disordersassociated with diabetes. Surprisingly, treatment of diabetes associatedwith hypertension with the combination of valsartan and a CCB,especially a non-DHP, preferably verapamil, proved to result in theconsiderable reduction of sudden death events and consequently in asignificant degree of increase of the survival rate in the experimentalmodel using diabetic SHRs.

Diabetes is induced in SHRs aged about 6 to 8 weeks weighing about 250to 300 g by treatment e.g. with streptozotocin. The drugs areadministered by twice daily average. Untreated diabetic SHRs are used ascontrol group (group 1). Other groups of diabetic SHRs are treated with30 mg/kg of valsartan (group 2), with 20 mg/kg of verapamil (group 3)and with a combination of 20 mg/kg of valsartan and 15 mg/kg ofverapamil (group 4). On a regular basis, besides other parameters thesurvival rate after 21 weeks of treatment is being monitored. In week 21of the study, following survival rates have been determined:

Test Group Survival Rate [%] 1 29.7 2 45.9 3 42.9 4 67.1

The results of this study clearly show, that though CCBs are notnormally used for the treatment of hypertension in diabetic patients,not only the blood pressure is reduced but moreover the survival rate isdrastically increased when administering to diabetic SHRs a combinationof valsartan and verapamil (the amounts of both components in thecombination being reduced versus the amounts of the single drugs whenadministered alone). The increased survival seen in diabetic SHR isconsistent with an attenuation of end-organ damage. Accordingly, thecombination of valsartan and a CCB may be used for the treatment (andalso for the prevention) of diabetes, e.g. of hypertension in diabeticpatients, especially in hypertensive patients with NIDDM, and may beused for slowing the progression of diabetic renal diseases, such asdiabetic nephropathy associated with NIDDM, and for reducing proteinuriain diabetic patients.

It is the object of this invention to provide a pharmaceuticalcombination composition, e.g. for the treatment or prevention of acondition or disease selected from the group consisting of hypertension,(acute and chronic) congestive heart failure, left ventriculardysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy,supraventricular and ventricular arrhythmias, atrial fibrillation oratrial flutter, myocardial infarction and its sequelae, atherosclerosis,angina (whether unstable or stable), renal insufficiency (diabetic andnon-diabetic), heart failure, angina pectoris, diabetessecondaryaldosteronism, primary and secondary pulmonary hyperaldosteronism,primary and pulmonary hypertension, renal failure conditions, such asdiabetic nephropathy, glomerulonephritis, scleroderma, glomerularsclerosis, proteinuria of primary renal disease, and also renal vascularhypertension, diabetic retinopathy, the management of other vasculardisorders, such as migraine, Raynaud's disease, luminal hyperplasia,cognitive dysfunction (such as Alzheimer's), and stroke whichcomposition comprises (i) the AT₁-antagonists valsartan or apharmaceutically acceptable salt thereof and (ii) a CCB or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In this composition, components (i) and (ii) can be obtained andadministered together, one after the other or separately in one combinedunit dose form or in two separate unit dose forms. The unit dose formmay also be a fixed combination.

A further aspect of the present invention is the use a pharmaceuticalcomposition comprising (i) the AT₁-antagonists valsartan or apharmaceutically acceptable salt thereof and (ii) a CCB or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier for the manufacture of a therapeutically effectivepharmaceutical composition for the treatment or prevention of acondition or disease selected from the group consisting of hypertension,(acute and chronic) congestive heart failure, left ventriculardysfunction and hypertrophic cardiomyopathy, myocardial infarction andits sequelae, supraventricular and ventricular arrhythmias, atrialfibrillation or atrial flutter, atherosclerosis, stable angina (whetherstabel or unstable), renal insufficiency (diabetic and non-diabetic),heart failure, angina pectoris, diabetessecondary aldosteronism, primaryand secondary pulmonary hyperaldosteronism, primary and pulmonaryhypertension, renal failure conditions, such as diabetic nephropathy,glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria ofprimary renal disease, and also renal vascular hypertension, diabeticretinopathy, the management of other vascular disorders, such asmigraine, Raynaud's disease, luminal hyperplasia, cognitive dysfunction(such as Alzheimer's), and stroke

A further aspect of the present invention is a method for the treatmentor prevention of a condition or disease selected from the groupconsisting of hypertension, (acute and chronic) congestive heartfailure, left ventricular dysfunction and hypertrophic cardiomyopathy,myocardial infarction and its sequelae, supraventricular and ventriculararrhythmias, atrial fibrillation or atrial flutter, atherosclerosis,angina (whether stable or ustable), renal insufficiency (diabetic andnon-diabetic), heart failure, angina pectoris, diabetessecondaryaldosteronism, primary and secondary pulmonary hyperaldosteronism,primary and pulmonary hypertension, renal failure conditions, such asdiabetic nephropathy, glomerulonephritis, scleroderma, glomerularsclerosis, proteinuria of primary renal disease, and also renal vascularhypertension, diabetic retinopathy, the management of other vasculardisorders, such as migraine, Raynaud's disease, luminal hyperplasia,cognitive dysfunction (such as Alzheimer's), and stroke, comprisingadministering a therapeutically effective amount of combination of (i)the AT₁-antagonists valsartan or a pharmaceutically acceptable saltthereof and (ii) a CCB or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier to a mammal in need of suchtreatment.

A therapeutically effective amount of each of the component of thecombination of the present invention may be administered simultaneouslyor sequentially and in any order.

The corresponding active ingredient or a pharmaceutically acceptablesalt thereof may also be used in form of a hydrate or include othersolvents used for crystallization.

The pharmaceutical compositions according to the invention can beprepared in a manner known per se and are those suitable for enteral,such as oral or rectal, and parenteral administration to mammals(warm-blooded animals), including man, comprising a therapeuticallyeffective amount of the pharmacologically active compound, alone or incombination with one or more pharmaceutically acceptable carries,especially suitable for enteral or parenteral application.

The novel pharmaceutical preparations contain, for example, from about10% to about 80%, preferably from about 20% to about 60%, of the activeingredient. Pharmaceutical preparations according to the invention forenteral or parenteral administration are, for example, those in unitdose forms, such as sugar-coated tablets, tablets, capsules orsuppositories, and furthermore ampoules. These are prepared in a mannerknown per se, for example by means of conventional mixing, granulating,sugar-coating, dissolving or lyophilizing processes. Thus,pharmaceutical preparations for oral use can be obtained by combiningthe active ingredient with solid carriers, if desired granulating amixture obtained, and processing the mixture or granules, if desired ornecessary, after addition of suitable excipients to give tablets orsugar-coated tablet cores.

The determination of the dose of the active ingredients necessary toachieve the desired therapeutic effect is within the skill of those whopractice in the art. The dose depends on the warm-blooded animalspecies, the age and the individual condition and on the manner ofadministration. In the normal case, an approximate daily dose in thecase of oral administration for a patient weighing approximately 75 kgfor oral application is of about 10 mg to about 200 mg, especially about20 to about 120 mg, most preferably about 40 mg to about 80 mg forvalsartan and about 1.0 mg to about 180 mg, preferably about 2.5 mg toabout 50 mg, for the CCB, depending on the specific CCB.

The following example illustrates the invention described above;however, it is not intended to limit its extent in any manner.

Valsartan Tablet Formulation 80 mg+Amlodipine 5 mg (Rollercompaction)

Dosage (mg) 80 mg Valsartan + 5 mg Amlodipine Diameter (mm) 9 Shaperound Breaking line without Tablet-weight (mg) 215

Formulation of the Tablet Valsartan 80 mg+Amlodipine 5 mg

80 mg Valsartan + Function of the Excipient in 5 mg Amlodipine DosageStrength the Formulation mg: I. Compactate 1. Valsartan DS drugsubstance 80.0 2. Amlodipine DS drug substance 5.0 3. Avicel PH 102filler 104.0 4. PVPP-XL disintegrant 20.0 5. Aerosil 200 glidant 0.75 6.Magnesium- lubricant 2.5 stearate II. Outer Phase 7. Aerosil 200 glidant0.75 8. magnesium- lubricant 2.0 stearate total 215.0

What is claimed is:
 1. A method for the treatment or prevention ofhypertension associated with diabetes comprising administering atherapeutically effective amount of a combination consisting essentiallyof (i) the AT₁-antagonist valsartan or a pharmaceutically acceptablesalt thereof and (ii) the Calcium channel blocker amlodipine or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier to a mammal in need thereof.
 2. A pharmaceuticalcombination composition consisting essentially of (i) the AT₁-antagonistvalsartan or a pharmaceutically acceptable salt thereof and (ii) theCalcium channel blocker amlodipine or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 3. A pharmaceuticalcombination composition as claimed in claim 2 for oral application,comprising of about 10 mg to about 200 mg of valsartan.
 4. Apharmaceutical combination composition as claimed in claim 2 for oralapplication, comprising about 1.0 mg to about 180 mg of the Calciumchannel blocker amlodipine.